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1.
Artigo em Inglês | MEDLINE | ID: mdl-33588688

RESUMO

The ability to generate associative representations and to retrieve them from long-term episodic memory generally declines in healthy aging. However, it is unclear whether healthy aging has differential effects on associative memory for identity, spatial configuration, and temporal order relationships. In the current study, we assessed how healthy aging impacts on associative memory for identity, spatial, or temporal relationships between pairs of visual objects via discrimination of intact and rearranged pairs. Accuracy and response time performance of healthy older adults (aged 65-80) were compared with young adults (ages 19-30). Age-related declines in associative memory were observed equally for all types of associations, but these declines differed by associative status: aging most strongly affected ability to discriminate rearranged pairs. These results suggest that associative memory for identity, spatial, and temporal relationships are equally affected by healthy aging, and may all depend on a shared set of basic associative mechanisms.

2.
BMC Med Genomics ; 14(1): 45, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568140

RESUMO

BACKGROUND: Coronary artery calcification (CAC) is a noninvasive measure of coronary atherosclerosis, the proximal pathophysiology underlying most cases of myocardial infarction (MI). We sought to identify expression signatures of early MI and subclinical atherosclerosis in the Framingham Heart Study (FHS). In this study, we conducted paired-end RNA sequencing on whole blood collected from 198 FHS participants (55 with a history of early MI, 72 with high CAC without prior MI, and 71 controls free of elevated CAC levels or history of MI). We applied DESeq2 to identify coding-genes and long intergenic noncoding RNAs (lincRNAs) differentially expressed in MI and high CAC, respectively, compared with the control. RESULTS: On average, 150 million paired-end reads were obtained for each sample. At the false discovery rate (FDR) < 0.1, we found 68 coding genes and 2 lincRNAs that were differentially expressed in early MI versus controls. Among them, 60 coding genes were detectable and thus tested in an independent RNA-Seq data of 807 individuals from the Rotterdam Study, and 8 genes were supported by p value and direction of the effect. Immune response, lipid metabolic process, and interferon regulatory factor were enriched in these 68 genes. By contrast, only 3 coding genes and 1 lincRNA were differentially expressed in high CAC versus controls. APOD, encoding a component of high-density lipoprotein, was significantly downregulated in both early MI (FDR = 0.007) and high CAC (FDR = 0.01) compared with controls. CONCLUSIONS: We identified transcriptomic signatures of early MI that include differentially expressed protein-coding genes and lincRNAs, suggesting important roles for protein-coding genes and lincRNAs in the pathogenesis of MI.

3.
Clin Epigenetics ; 13(1): 43, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632303

RESUMO

BACKGROUND: Epigenetic alterations may contribute to early detection of cancer. We evaluated the association of blood DNA methylation with lymphatic-hematopoietic cancers and, for comparison, with solid cancers. We also evaluated the predictive ability of DNA methylation for lymphatic-hematopoietic cancers. METHODS: Blood DNA methylation was measured using the Illumina Infinium methylationEPIC array in 2324 Strong Heart Study participants (41.4% men, mean age 56 years). 788,368 CpG sites were available for differential DNA methylation analysis for lymphatic-hematopoietic, solid and overall cancers using elastic-net and Cox regression models. We conducted replication in an independent population: the Framingham Heart Study. We also analyzed differential variability and conducted bioinformatic analyses to assess for potential biological mechanisms. RESULTS: Over a follow-up of up to 28 years (mean 15), we identified 41 lymphatic-hematopoietic and 394 solid cancer cases. A total of 126 CpGs for lymphatic-hematopoietic cancers, 396 for solid cancers, and 414 for overall cancers were selected as predictors by the elastic-net model. For lymphatic-hematopoietic cancers, the predictive ability (C index) increased from 0.58 to 0.87 when adding these 126 CpGs to the risk factor model in the discovery set. The association was replicated with hazard ratios in the same direction in 28 CpGs in the Framingham Heart Study. When considering the association of variability, rather than mean differences, we found 432 differentially variable regions for lymphatic-hematopoietic cancers. CONCLUSIONS: This study suggests that differential methylation and differential variability in blood DNA methylation are associated with lymphatic-hematopoietic cancer risk. DNA methylation data may contribute to early detection of lymphatic-hematopoietic cancers.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33528568

RESUMO

Profound T-cell lymphopenia is the hallmark of severe Covid-19. T-cell proliferation is telomere length (TL)-dependent and telomeres shorten with age. Older Covid-19 patients, we hypothesize, are therefore at a higher risk of having TL-dependent lymphopenia. We measured TL by the novel Telomere Shortest Length Assay (TeSLA), and by Southern blotting of the terminal restriction fragments (SB) in peripheral blood mononuclear cells of 17 Covid-19 and 21 non-Covid-19 patients, aged 87 ± 8 (mean ± SD) and 87 ± 9 years, respectively. TeSLA tallies and measures single telomeres, including short telomeres undetected by SB. Such telomeres are relevant to TL-mediated biological processes, including cell viability and senescence. TeSLA yields two key metrics: the proportion of telomeres with different lengths (expressed in %), and their mean, TeSLA mTL (expressed in kb). Lymphocyte count (10 9/L) was 0.91 ± 0.42 in Covid-19 patients and 1.50 ± 0.50 in non-Covid-19 patients (P < 0.001). In Covid-19 patients, but not in non-Covid-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kb (P = 0.005) and positively correlated with TeSLA mTL (P = 0.03). Lymphocyte count was not significantly correlated with SB mTL in either Covid-19 or non-Covid-19 patients. We propose that compromised TL-dependent T-cell proliferative response, driven by short telomere in the TL distribution, contributes to Covid-19 lymphopenia among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons.

6.
J Am Heart Assoc ; 10(1): e018020, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33372532

RESUMO

Background Proteomic biomarkers related to cardiovascular disease risk factors may offer insights into the pathogenesis of cardiovascular disease. We investigated whether modifiable lifestyle risk factors for cardiovascular disease are associated with distinctive proteomic signatures. Methods and Results We analyzed 1305 circulating plasma proteomic biomarkers (assayed using the SomaLogic platform) in 897 FHS (Framingham Heart Study) Generation 3 participants (mean age 46±8 years; 56% women; discovery sample) and 1121 FOS (Framingham Offspring Study) participants (mean age 52 years; 54% women; validation sample). Participants were free of hypertension, diabetes mellitus, and clinical cardiovascular disease. We used linear mixed effects models (adjusting for age, sex, body mass index, and family structure) to relate levels of each inverse-log transformed protein to 3 lifestyle factors (ie, smoking, alcohol consumption, and physical activity). A Bonferroni-adjusted P value indicated statistical significance (based on number of proteins and traits tested, P<4.2×10-6 in the discovery sample; P<6.85×10-4 in the validation sample). We observed statistically significant associations of 60 proteins with smoking (37/40 top proteins validated in FOS), 30 proteins with alcohol consumption (23/30 proteins validated), and 5 proteins with physical activity (2/3 proteins associated with the physical activity index validated). We assessed the associations of protein concentrations with previously identified genetic variants (protein quantitative trait loci) linked to lifestyle-related disease traits in the genome-wide-association study catalogue. The protein quantitative trait loci were associated with coronary artery disease, inflammation, and age-related mortality. Conclusions Our cross-sectional study from a community-based sample elucidated distinctive sets of proteins associated with 3 key lifestyle factors.

7.
Nucleic Acids Res ; 49(1): 529-546, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33313837

RESUMO

A species-specific region, denoted SpG8-1b allowing hydroxycinnamic acids (HCAs) degradation is important for the transition between the two lifestyles (rhizospheric versus pathogenic) of the plant pathogen Agrobacterium fabrum. Indeed, HCAs can be either used as trophic resources and/or as induced-virulence molecules. The SpG8-1b region is regulated by two transcriptional regulators, namely, HcaR (Atu1422) and Atu1419. In contrast to HcaR, Atu1419 remains so far uncharacterized. The high-resolution crystal structures of two fortuitous citrate complexes, two DNA complexes and the apoform revealed that the tetrameric Atu1419 transcriptional regulator belongs to the VanR group of Pfam PF07729 subfamily of the large GntR superfamily. Until now, GntR regulators were described as dimers. Here, we showed that Atu1419 represses three genes of the HCAs catabolic pathway. We characterized both the effector and DNA binding sites and identified key nucleotides in the target palindrome. From promoter activity measurement using defective gene mutants, structural analysis and gel-shift assays, we propose N5,N10-methylenetetrahydrofolate as the effector molecule, which is not a direct product/substrate of the HCA degradation pathway. The Zn2+ ion present in the effector domain has both a structural and regulatory role. Overall, our work shed light on the allosteric mechanism of transcription employed by this GntR repressor.


Assuntos
Agrobacterium/metabolismo , Proteínas de Bactérias/fisiologia , Ácidos Cumáricos/metabolismo , Família Multigênica , Proteínas Repressoras/fisiologia , Agrobacterium/genética , Regulação Alostérica , Proteínas de Bactérias/genética , Proteínas de Bactérias/isolamento & purificação , Sítios de Ligação , Cristalografia por Raios X , Regulação Bacteriana da Expressão Gênica , Genes Sintéticos , Modelos Moleculares , Regiões Promotoras Genéticas/genética , Conformação Proteica , Domínios Proteicos , Multimerização Proteica , Proteínas Repressoras/genética , Proteínas Repressoras/isolamento & purificação , Citrato de Sódio , Tetra-Hidrofolatos/fisiologia , Zinco/fisiologia
8.
Arterioscler Thromb Vasc Biol ; : ATVBAHA120315186, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33297754

RESUMO

OBJECTIVE: Adiposity is associated with oxidative stress, inflammation, and glucose intolerance. Previous data suggest that platelet gene expression is associated with key cardiometabolic phenotypes, including body mass index but stable in healthy individuals over time. However, modulation of gene expression in platelets in response to metabolic shifts (eg, weight reduction) is unknown and may be important to defining mechanism. Approach and Results: Platelet RNA sequencing and aggregation were performed from 21 individuals with massive weight loss (>45 kg) following bariatric surgery. Based on RNA sequencing data, we measured the expression of 67 genes from isolated platelet RNA using high-throughput quantitative reverse transcription quantitative PCR in 1864 FHS (Framingham Heart Study) participants. Many transcripts not previously studied in platelets were differentially expressed with bariatric surgical weight loss, appeared specific to platelets (eg, not differentially expressed in leukocytes), and were enriched for a nonalcoholic fatty liver disease pathway. Platelet aggregation studies did not detect alteration in platelet function after significant weight loss. Linear regression models demonstrated several platelet genes modestly associated with cross-sectional cardiometabolic phenotypes, including body mass index. There were no associations between studied transcripts and incident diabetes or cardiovascular end points. CONCLUSIONS: In summary, while there is no change in platelet aggregation function after significant weight loss, the human platelet experiences a dramatic transcriptional shift that implicates pathways potentially relevant to improved cardiometabolic risk postweight loss (eg, nonalcoholic fatty liver disease). Further studies are needed to determine the mechanistic importance of these observations.

9.
Clin EEG Neurosci ; : 1550059420973107, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33207955

RESUMO

How can the stability of a recently acquired memory be improved? Recent findings regarding the importance of theta frequency EEG activity in the hippocampus suggest that entraining neural activity in that frequency band might increase post-encoding waking replay, reinforcing learning-related plasticity. Our previous studies revealed that upregulating postlearning theta power using EEG neurofeedback (NFB) significantly benefitted procedural and episodic memory performance (both immediate and delayed), and may provide optimal conditions for stabilization of new memories. We have now explored whether memory benefits of theta NFB generalize to delayed spatial memory, an additional hippocampus-dependent process. Participants learned to associate object images with locations on a computer screen. NFB was used to enable participants to selectively increase scalp EEG theta power for 30 minutes. Visuo-spatial memory was tested one week later, with the theta NFB participants compared with 2 control groups (beta-augmentation NFB as an active control group, and an additional passive control group that did not engage in NFB). Theta upregulation was found to improve visuo-spatial memory, as reflected in reduced error distances in location marking and faster reaction time for correct answers by the theta group. This supports the contention that theta upregulation immediately after learning strengthens early consolidation of visuo-spatial memory. This intervention could potentially benefit various memory-challenged populations, as well as healthy individuals.

10.
Circ Res ; 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33092465

RESUMO

Rationale: Previous translational studies implicate plasma extracellular microRNA-30d (miR-30d) as a biomarker in left ventricular (LV) remodeling and clinical outcome in heart failure (HF) patients, though precise mechanisms remain obscure. Objective: To investigate the mechanism of miR-30d-mediated cardioprotection in HF. Methods and Results: In rat and mouse models of ischemic HF, we show that miR-30d gain of function (genetic, lentivirus or agomiR-mediated) improves cardiac function, decreases myocardial fibrosis, and attenuates cardiomyocyte (CM) apoptosis. Genetic or locked nucleic acid (LNA)-based knock-down of miR-30d expression potentiates pathological LV remodeling, with increased dysfunction, fibrosis, and CM death. RNA-seq of in vitro miR-30d gain and loss of function, together with bioinformatic prediction and experimental validation in cardiac myocytes and fibroblasts, were used to identify and validate direct targets of miR-30d. miR-30d expression is selectively enriched in CMs, induced by hypoxic stress and is acutely protective, targeting mitogen-associate protein kinase (MAP4K4) to ameliorate apoptosis. Moreover, miR-30d is secreted primarily in extracellular vesicles by CMs and inhibits fibroblast proliferation and activation by directly targeting integrin α5 in the acute phase via paracrine signaling to cardiac fibroblasts. In the chronic phase of ischemic remodeling, lower expression of miR-30d in the heart and plasma EVs is associated with adverse remodeling in rodent models and human subjects, and is linked to whole blood expression of genes implicated in fibrosis and inflammation, consistent with observations in model systems. Conclusions: These findings provide the mechanistic underpinning for the cardioprotective association of miR-30d in human HF. More broadly, our findings support an emerging paradigm involving intercellular communication of EV-contained miRNAs to trans regulate distinct signaling pathways across cell types. Functionally validated RNA biomarkers and their signaling networks may warrant further investigation as novel therapeutic targets in HF.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33080140

RESUMO

RATIONALE: The association between aging and idiopathic pulmonary fibrosis is established. The associations between aging-related biomarkers and interstitial lung abnormalities (ILA) have not been comprehensively evaluated. OBJECTIVE: Evaluate associations between aging biomarkers, ILA, and all-cause mortality. METHODS: In the Framingham Heart Study (FHS), we evaluated associations between plasma biomarkers (interleukin-6 [IL-6], C-reactive protein [CRP], tumor necrosis factor alpha receptor II [TNFR], growth differentiation factor 15 [GDF15], cystatin-C, hemoglobin A1C [HGBA1C], insulin, insulin like growth factor [IGF] 1, and IGF binding proteins 1 and 3 [IGFBP1 and 3]), ILA, and mortality. Causal inference analysis was used to determine if biomarkers mediated age. GDF15 results were replicated in COPDGene. MEASUREMENTS AND MAIN RESULTS: In FHS, there was higher odds of ILA per increase in natural log-transformed (ln) GDF15 (OR [95% CI] = 3.4 [1.8-6.4], p=0.0002), TNFR (3.1 [1.6-5.8], p=0.004), IL-6 (1.8 [1.4-2.4], p<0.0001), and CRP (1.7 [1.3-2.0], p<0.0001). In FHS, after adjustment for multiple comparisons, no biomarker was associated with increased mortality, but GDF15 (HR = 2.0 [1.1-3.5], P=0.02), TNFR (1.8 [1.0-3.3], p=0.05), and IGFBP1 (1.3 [1.1-1.7], P=0.01) approached significance. In COPDGene, higher ln(GDF15) was associated with ILA (OR = 8.1 [3.1-21.4], p<0.0001) and mortality (HR = 1.6 [1.1-2.2], p=0.01). Causal inference analysis showed the association of age with ILA was mediated by IL-6 (p<0.0001), TNFR (p=0.002), and likely GDF15 (p=0.008) in FHS, and by GDF15 (p=0.001) in COPDGene. CONCLUSIONS: Some aging-related biomarkers are associated with ILA. GDF15, in particular, may explain some of the association between age, ILA, and mortality.

12.
Genet Epidemiol ; 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33038041

RESUMO

Multiple methods have been proposed to aggregate genetic variants in a gene or a region and jointly test their association with a trait of interest. However, these joint tests do not provide estimates of the individual effect of each variant. Moreover, few methods have evaluated the joint association of multiple variants with DNA methylation. We propose a method based on linear mixed models to estimate the joint and individual effect of multiple genetic variants on DNA methylation leveraging genomic annotations. Our approach is flexible, can incorporate covariates and annotation features, and takes into account relatedness and linkage disequilibrium (LD). Our method had correct Type-I error and overall high power for different simulated scenarios where we varied the number and specificity of functional annotations, number of causal and total genetic variants, frequency of genetic variants, LD, and genetic variant effect. Our method outperformed the family Sequence Kernel Association Test and had more stable estimations of effects than a classical single-variant linear mixed-effect model. Applied genome-wide to the Framingham Heart Study data, our method identified 921 DNA methylation sites influenced by at least one rare or low-frequency genetic variant located within 50 kilobases (kb) of the DNA methylation site.

13.
medRxiv ; 2020 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-33024983

RESUMO

BACKGROUND: Lymphopenia due to a plummeting T-cell count is a major feature of severe COVID-19. T-cell proliferation is telomere length (TL)-dependent and TL shortens with age. Older persons are disproportionally affected by severe COVID-19, and we hypothesized that those with short TL have less capacity to mount an adequate T-cell proliferative response to SARS-CoV-2. This hypothesis predicts that among older patients with COVID-19, shorter telomeres of peripheral blood mononuclear cells (PBMCs) will be associated with a lower lymphocyte count. METHODS: Our sample comprised 17 COVID-19 and 21 non-COVID-19 patients, aged 87(8) (mean(SD)) and 87 (9) years, respectively. We measured TL by the Telomere Shortest Length Assay, a novel method that measures and tallies the short telomeres directly relevant to telomere-mediated biological processes. The primary analysis quantified TL as the proportion of telomeres shorter than 2 kilobases. For comparison, we also quantified TL by Southern blotting, which measures the mean length of telomeres. RESULTS: Lymphocyte count (109/L) was 0.91 (0.42) in COVID-19 patients and 1.50(0.50) in non-COVID-19 patients (P < 0.001). In COVID-19 patients, but not in non-COVID-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kilobases (P = 0.005) and positively correlated with the mean of telomeres measured by TeSLA (P = 0.03). Lymphocyte counts showed no statistically significant correlations with Southern blotting results in COVID-19 or non-COVID-19 patients. CONCLUSIONS: These results support the hypothesis that a compromised TL-dependent T-cell proliferative response contributes to lymphopenia and the resulting disproportionate severity of COVID-19 among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons.

14.
Genome Med ; 12(1): 84, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32988399

RESUMO

BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. METHODS: To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9. RESULTS: Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10- 8). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10- 8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10- 12), as well as the TFAM knockout methylation (P = 4.41 × 10- 4) and expression (P = 4.30 × 10- 4) studies. CONCLUSIONS: These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

15.
J Am Heart Assoc ; 9(19): e014659, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32921207

RESUMO

Background GDF15 (growth differentiation factor 15) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may offer promise as biomarkers for cognitive outcomes, including dementia. We determined the association of these biomarkers with cognitive outcomes in a community-based cohort. Methods and Results Plasma GDF15 (n=1603) and NT-proBNP levels (n=1590) (53% women; mean age, 68.7 years) were measured in dementia-free Framingham Offspring cohort participants at examination 7 (1998-2001). Participants were followed up for incident dementia. Secondary outcomes included Alzheimer disease dementia, magnetic resonance imaging structural brain measures, and neurocognitive performance. During a median 11.8-year follow-up, 131 participants developed dementia. On multivariable Cox proportional-hazards analysis, higher circulating GDF15 was associated with an increased risk of incident all-cause and Alzheimer disease dementia (hazard ratio [HR] per SD increment in natural log-transformed biomarker value, 1.54 [95% CI, 1.22-1.95] and 1.37 [95% CI, 1.03-1.81], respectively), whereas higher plasma NT-proBNP was also associated with an increased risk of all-cause dementia (HR, 1.32; 95% CI, 1.05-1.65). Elevated GDF15 was associated with lower total brain and hippocampal volumes, greater white matter hyperintensity volume, and poorer cognitive performance. Elevated NT-proBNP was associated with greater white matter hyperintensity volume and poorer cognitive performance. Addition of both biomarkers to a conventional risk factor model improved dementia risk classification (net reclassification improvement index, 0.25; 95% CI, 0.05-0.45). Conclusions Elevated plasma GDF15 and NT-proBNP were associated with vascular brain injury on magnetic resonance imaging, poorer neurocognitive performance, and increased risk of incident dementia in individuals aged >60 years. Both biomarkers improved dementia risk classification beyond that of traditional clinical risk factors, indicating their potential value in predicting incident dementia.

16.
J Am Coll Cardiol ; 76(12): 1455-1465, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32943164

RESUMO

BACKGROUND: Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear. OBJECTIVES: The purpose of this study was to evaluate sex-specific associations of CV risk factors and biomarkers with incident HF. METHODS: The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio. RESULTS: Among 22,756 participants (mean age 60 ± 13 years, 53% women), HF occurred in 2,095 participants (47% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p < 0.001), and the combined clinical model had good discrimination in men (C-statistic = 0.80) and in women (C-statistic = 0.83). The majority of biomarkers were strongly and similarly associated with HF in both sexes. The clinical model improved modestly after adding natriuretic peptides in men (ΔC-statistic = 0.006; likelihood ratio chi-square = 146; p < 0.001), and after adding cardiac troponins in women (ΔC-statistic = 0.003; likelihood ratio chi-square = 73; p < 0.001). CONCLUSIONS: CV risk factors are strongly and similarly associated with incident HF in both sexes, highlighting the similar importance of risk factor control in reducing HF risk in the community. There are subtle sex-related differences in the predictive value of individual biomarkers, but the overall improvement in HF risk estimation when included in a clinical HF risk prediction model is limited in both sexes.

17.
Circ Res ; 127(9): 1182-1194, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-32781905

RESUMO

RATIONALE: Mean platelet volume (MPV) and platelet count (PLT) are platelet measures that have been linked to cardiovascular disease (CVD) and mortality risk. Identifying protein biomarkers for these measures may yield insights into CVD mechanisms. OBJECTIVE: We aimed to identify causal protein biomarkers for MPV and PLT among 71 CVD-related plasma proteins measured in FHS (Framingham Heart Study) participants. METHODS AND RESULTS: We conducted integrative analyses of genetic variants associated with PLT/MPV with protein quantitative trait locus variants associated with plasma proteins followed by Mendelian randomization to infer causal relations of proteins for PLT/MPV. We also tested protein-PLT/MPV association in FHS participants. Using induced pluripotent stem cell-derived megakaryocyte clones that produce functional platelets, we conducted RNA-sequencing and analyzed expression differences between low- and high-platelet producing clones. We then performed small interfering RNA gene knockdown experiments targeting genes encoding proteins with putatively causal platelet effects in megakaryocyte clones to examine effects on platelet production. In protein-trait association analyses, ten proteins were associated with MPV and 31 with PLT. Mendelian randomization identified 4 putatively causal proteins for MPV and 4 for PLT. GP-5 (Glycoprotein V), GRN (granulin), and MCAM (melanoma cell adhesion molecule) were associated with PLT, while MPO (myeloperoxidase) showed significant association with MPV in both analyses. RNA-sequencing analysis results were directionally concordant with observed and Mendelian randomization-inferred associations for GP-5, GRN, and MCAM. In siRNA gene knockdown experiments, silencing GP-5, GRN, and MPO decreased PLTs. Genome-wide association study results suggest several of these may be linked to CVD risk. CONCLUSIONS: We identified 4 proteins that are causally linked to PLTs. These proteins may also have roles in the pathogenesis of CVD via a platelet/blood coagulation-based mechanism.

18.
Aging (Albany NY) ; 12(14): 14092-14124, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32697766

RESUMO

DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to SERINC2, CHST12, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.

19.
Curr Biol ; 30(11): R637-R639, 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32516610

RESUMO

Sizes of intracellular structures are important for function, yet mechanisms underlying subcellular size control are largely unexplored. A new study reveals how differences in tubulin populations between two related Xenopus frog species influence microtubule dynamics and spindle length.

20.
Circ Genom Precis Med ; 13(4): e002766, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32525743

RESUMO

BACKGROUND: DNA methylation patterns associated with habitual diet have not been well studied. METHODS: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality. RESULTS: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected P<1.6×10-3). Hypermethylation of cg18181703 (SOCS3) was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (P=5.7×10-15). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (P<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR P<4.5×10-4). For example, hypermethylation of cg11250194 (FADS2) was associated with lower triglyceride concentrations (MR, P=1.5×10-14).and hypermethylation of cg02079413 (SNORA54; NAP1L4) was associated with body mass index (corrected MR, P=1×10-6). CONCLUSIONS: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.

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